ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4861 of the RYR1 protein (p.Arg4861Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neonatal onset myopathy as well as central core disease (CCD) (PMID: 12565913, 17483490, 23553484, 25960145, 26684984). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 65986). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg4861 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11709545, 12565913, 16621918, 23394784, 25521991). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.